Inoue Masayuki, Mimura Kousaku, Izawa Shinichiro, Shiraishi Kensuke, Inoue Ayako, Shiba Shugo, Watanabe Mitsuaki, Maruyama Takanori, Kawaguchi Yoshihiko, Inoue Shingo, Kawasaki Tomonori, Choudhury Aniruddha, Katoh Ryohei, Fujii Hideki, Kiessling Rolf, Kono Koji
First Department of Surgery; University of Yamanashi; Yamanashi, Japan.
Oncoimmunology. 2012 Oct 1;1(7):1104-1110. doi: 10.4161/onci.21056.
HER2 is a promising target for immunotherapeutic interventions with T cell-based approaches since it is amplified and overexpressed in 20-30% of breast cancers. However, several previous studies including ours showed that HER2-overexpressing tumors may escape cytotoxic T lymphocyte-mediated lysis by downregulating MHC Class I and components of the antigen-processing machinery. The aims of the present study were to analyze the relationship between HER2 and MHC Class I expression and to elucidate the mechanisms underlying MHC Class I downregulation in breast cancer. We explored expression of HER2, MHC Class I, PTEN, Ki67, estrogen and progesterone expression in 70 breast cancer patients by immunohistochemistry (IHC) and analyzed their correlation. We also explored the components of the signal transduction pathway that are involved in the regulation of MHC Class I expression using small-interfering RNAs targeting HER2 as well as an inhibitor of HER2 signaling. HER2 expression in breast cancers correlated inversely with MHC Class I expression analyzed by IHC. HER2 depletion by small-interfering RNAs resulted in MHC Class I upregulation. Moreover, MHC Class I expression on breast cancer cell lines was upregulated by PD98059, an inhibitor of mitogen-associated protein kinases, in a dose-dependent manner. Thus, agents that target the MAPK signaling pathway may increase MHC Class I expression in breast cancer cells.
HER2是基于T细胞方法的免疫治疗干预的一个有前景的靶点，因为它在20%-30%的乳腺癌中发生扩增和过表达。然而，包括我们的研究在内，之前的几项研究表明，HER2过表达的肿瘤可能通过下调MHC I类分子和抗原加工机制的成分来逃避细胞毒性T淋巴细胞介导的裂解。本研究的目的是分析HER2与MHC I类分子表达之间的关系，并阐明乳腺癌中MHC I类分子下调的潜在机制。我们通过免疫组织化学（IHC）检测了70例乳腺癌患者中HER2、MHC I类分子、PTEN、Ki67、雌激素和孕激素的表达，并分析了它们之间的相关性。我们还使用靶向HER2的小干扰RNA以及HER2信号抑制剂，探索了参与MHC I类分子表达调控的信号转导通路的成分。通过IHC分析，乳腺癌中的HER2表达与MHC I类分子表达呈负相关。小干扰RNA介导的HER2缺失导致MHC I类分子上调。此外，丝裂原活化蛋白激酶抑制剂PD98059可使乳腺癌细胞系中的MHC I类分子表达呈剂量依赖性上调。因此，靶向MAPK信号通路的药物可能会增加乳腺癌细胞中MHC I类分子的表达。
